SUMMARY Inflammatory breast cancer (IBC, ~5% of all breast cancers) is the most lethal form of breast cancer presenting a 5-year survival rate that is less than the half of the non-IBC patients. Furthermore, its mortality has continued to increase during the last 20 years. Despite these facts, IBC remains poorly understood and systemic disease management relies exclusively on chemotherapy. Remarkably, we have found that survival of IBC cells depend on histone deacetylase 6 (HDAC6) function while non-IBC cells are mainly independent. Importantly, we have demonstrated that the leading HDAC6 inhibitor (Rocilinostat/ACY1215, Acetylon Inc), which is currently being tested in clinical trials for other tumors presents anticancer activity in IBC cells in preclinical models. Our findings represent an opportunity to develop novel targeted therapies for IBC patients. Hypothesis and Objective: We hypothesize that key biological processes regulated by HDAC6 are essential to maintain the homeostasis of IBC cells. In this proposal our goal is to characterize the mechanisms involved in the addiction of IBC cells to HDAC6 function in order to be able to transition our finding to the clinic. Specific Aim1. Uncover the molecular mechanisms by which HDAC6 regulate the homeostasis of IBC cells. HDAC6 is a class-IIB histone deacetylase with a critical function on the cell's response to accumulation of misfolded proteins and damaged mitochondria due to its role in formation of aggresome, mito-aggresome and autophagy. We will study if the lethality seen in IBC cells is due to loss of canonical functions or a different one. -Aim 1.a) Evaluate the function of HDAC6 in the metabolism of toxic bioproducts. -Aim 1.b) Evaluate the function of HDAC6 in basal autophagy. -Aim 1.b) Investigate novel putative HDAC6 substrates. Specific Aim2. Design and evaluation of combination therapy with HDAC6 inhibition for IBC treatment. Systemic therapy combining different anticancer agents is generally needed in epithelial cancer to achieve maximum therapeutic benefit. Here, we hypothesize that combinatorial therapy will circumvent resistance to monotherapy based on HDAC6 inhibition. We will perform both candidate based and unbiased studies to optimize the anticancer activity of regimens containing HDAC6 inhibitors. -Aim 2.a) Candidate based therapy using chemotherapy plus HDAC6 inhibition. -Aim 2.b) Unbiased system biology studies for the identification of Master Regulators (MR) associated with the response to HDAC6 inhibition. Significance. This proposal represents the preclinical studies necessary to translate our findings into targeted therapy for IBC patients. The importance of our proposal is that it could lead to a decrease in mortality from the most lethal and one the less characterized group of breast cancers.